Role of estrogen receptors in pancreatic beta-cell survival and insulin secretion

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In diabetes, the death of insulin-producing ß-cells in the pancreas by apoptosis leads to insulin dependence. Yet, the events that promote ß-cell death are still not fully understood. It is essential to increase our basic knowledge of the processes regulating beta-cell survival in order to develop novel and efficient therapies for diabetic patients. Evidence suggests that the female hormone, 17 ß-estradiol (estradiol), protects insulin production and prevents diabetes. Although estradiol acts primarily via two distinct estrogen receptors (ERs), ERalpha and ERbeta, recently, the G protein-coupled estrogen receptor (GPER), also called GPR30 has been recognized as a putative membrane receptor for estrogens that mediates a series of non-genomic E2 signals. The individual contributions of these ERs in protecting ß-cell survival have not been established. Our objective for this exploratory application is to elucidate the contribution played by non-classical estrogen actions via GPER in ß-cell survival in vivo, through the use of genetic mouse models. We will use a combined ß-cell specific ERalpha/ERbeta deficient mouse (ßERabKO) and a GPER deficient mouse. Using these tools, in combination with pharmacological probes, we will study the role of GPER actions in beta-cell survival in vivo and in cultured islet. Through the proposed research - which is the first investigation of rapid, non genomic ERs in ß-cell survival in vivo - we plan to demonstrate that GPER is important to ß-cell survival in vivo, and therefore represent a viable targets for therapeutic intervention.